Ethyl fluoro-(2-dibenzofuranyl)-acetate

ABSTRACT

A new class of derivatives of the ethyl ester of fluoroacetic acid is described and some methods for their preparation are reported. The compounds have a pharmacological interest, because of their marked antiinflammatory activity.

United States Patent Cavalleri et al.

[ 1 Feb. 11,1975

ETl-IYL FLUORO-(2-DIBENZOFURANYL)- ACETATE Inventors: Bruno Cavalleri, Milan; Elvio Bellasio, Albate, both of Italy; Emilio Testa, Ticino, Switzerland; Giulio Maffii, Milan, Italy Lepetit S.p.A.Gruppo per la Ricerca Scientifica e la Produzione Chemica Farmaceutica, Milan, Italy Filed: Aug. 28, 1972 Appl. No.: 284,090

Related U.S. Application Data Division of Set. No. 750,009, Aug. 5, 1968, Pat. No. 3,699,151.

Assignee:

Foreign Application Priority Data Aug. 14, 1967 Great Britain 37197/67 [52] U.S. Cl 260/3462 M [51] Int. Cl C07d 5/44 [58] Field of Search 260/3462 M [56] References Cited OTHER PUBLICATIONS Cavalleri et 211.. Chemical Abstracts, 1969, vol. 71.

Primary Examiner.lohn D. Randolph Assistant ExaminerBernard Dentz Attorney, Agent, or Firm-Joseph IHirsehmann 1 Claim, No Drawings ETHYL Fl.ll()R(Hg-DlBlQZQFURANYlJ-ACEfIAflE 7 This application is a division of our co-pending application Serial No. 750,009 filed August th, 1968, now

' Patent No. 3,699,151, dated October 17th, 1972.

This invention is concerned with a new class of compounds and with the methods for preparing them. More particularly the compounds of the invention are represented by the following general formula:

wherein R is a member of the class consisting of aryl dibenzofuranyl, and a radical having the formula wherein R is selected from lower alkyl and lower alkoxy, the term lower having the significance ofwith 1-8 carbon atoms."

The compounds of the invention can be prepared according to one of the following methods:

A. A diethyl malonate of the formula COOCzHa R" HF OOCQIH wherein R has the above significance, is reacted with an equimolecular amount of an alkali metal hydroxide in absolute ethanol at a room temperature.

COOC2H XOH R"- HF R-CHF-COOCzHs CzH5OH QOCzHs The symbol X represents an alkali metal.

B. The process consists in contacting a solution of a compound, having the general formula C O OMe R- HF OOCalIs wherein R has the above significance and Me represents an alkali metal atom, in an organic, inert and anhydrous solvent, with a cationic, ion-exchange resin at a temperature of about 50-75.

COOMe resm R- HF R-CHF-COOCzHs OOCzHs C. A compound of the general formula wherein R has the above significance, is reacted with 2-chloro-1,l,2-trifluoro-triethylamine, in an inert organic anhydrous solvent. Though the reaction takes place with about equimolecular amounts of the two reactants, it is preferred to use a more or less important excess of the second reactant.

R-- CI-I-COOCzIIs The compounds of the invention proved interesting for their antiinflamrnatory activity. This property was evaluated through the known carrageenin induced edema test in rats. We used for our experiments Wistar .female rats of 120-150 g. body weight.

treatment. Immediately thereafter the volume of the injected paw was measured by mean sof a plathysmograph and the measure repeated 3 hours later.

The increase in foot volume represents the degree of the developed edema.

By comparing the edema of the treated animals with that of the controls, it is possible to evaluate thee effectiveness of the tested drugs. The following table 1 reports the results obtained with some compounds of the invention, expressed as percent decrease of the edema in the treated animals with respect to the controls. The

toxicities are also given for a better evaluation of thesafety of the compounds.

TABLE 1 Compound of LD mg/kg Dose mg/kg Carrageenin example i.p., in mice 05, in rats edema Decrease The following non limitative examples illustrate the invention.

EXAMPLE 1 Preparation of ethyl fluoro(p-methoxyphenyl)-acetate 1. According to method A.

To a solution of 1.3 g. (4.5 mmole) of diethyl fluoro(' p-methoxyphenyl)-malonate, in 100 ml. of absolute ethanol, 8.5 ml. ofa 3 percent ethanolic solution of potassium hydroxide are added during 6 hours at room temperature. At the end of the reaction, 1 liter of diethyl ether is added and the mixture is allowed to stand overnight. A precipitate consisting of the monopotassium salt of the monoethyl flouro(p-methoxyphenyl)- malonate is formed. After filtering, the solution is concentrated to dryness. The residue is distilled and the fraction boiling at 100-105C/0.2 mm. is collected. 2. According to method B.

An amount of 340 ml. of amberlite IR 120 (H), previously washed with absolute ethanol, is transferred into a water-jacketed glass tube, 60 cm. long and of 3 cm. inside diameter, and hot absolute ethanol is added, until the top of the column is covered by the liquid. While water at 60C is circulated into the jacket, 21 hot solution containing 10 g. of monopotassium salt of the monoethyl fluoro(p-methoxyphenyl)-malonate dissolved in 1.4 liters of absolute ethanol, is slowly poured onto the top of the column, collecting at the same time the eluate. When all the solution has been added, the column is washed with hot ethanol, and the eluate concentrated in vacuo at a temperature not exceeding 50C. The residue is taken up with diethyl ether and quickly washed with a 10 percent aqueous solution of sodium bicarbonate. The organic phase is dried over sodium sulphate and the solvent removed with the aid of vacuum in an evaporator. The residue is distilled at l-l05C/0.2 mm., avoiding overheating. A colorless oil is obtained, consisting of ethyl fluoro(pmethoxphenyl)-acetate. Yield 77.8 percent, n 1,5133.

Calcd. for C H FO C, 62,25; H, 6, Found: H 6

3. According to method C.

To a solution of 11.65 g. (55 mmole) of ethyl-pmethoxymandelate in 150 ml. of anhydrous methylene chloride, 20.8 g. (0.11 mole) of 2-chloro-1,1,2-trifluoro-triethylamine are added. The solution is allowed to stand overnight at C, then for 5 more hours at room temperature. It is then washed with a saturated sodium carbonate solution, and successively with water, dried over anhydrous sodium sulphate and concentrated. A residue is obtained which is distilled in vacuo, collecting the fraction boiling at lOO-l06C/0.2 mm. An amount of 8.6 g. of ethyl fluoro (p-methoxyphenyl)-acetate is obtained. Yield 73.8 percent.

Calcd. for C H F 11 Found:

EXAMPLE 2 Preparation of ethyl p-ethoxyphenyl(fluoro)-acetate.

1. According to method A To a solution of 4.3 g. (14 mmole) of diethyl pethoxyphenyl (fluoro)-malonate in 30 ml. of absolute ethanol, 28 ml. of a 3 percent ethanolic solution of potassium hydroxide (14 mmole) are added during 7 hours at room temperature. Then, 3 liters of diethyl ether are added and the mixture is allowed to stand overnight. A precipitate of monopotassium salt of the monoethyl p-ethoxyphenyl (fluoro)-malonate is formed and filtered off. The solution is concentrated to dryness in vacuo. The residue is distilled, collecting the fraction boiling at 100-l05C/0.2 mm. 2. According to method B.

A solution of 10 g. (32 mmole) of the monopotassium salt of the monoethyl p-ethoxyphenyl(fluoro)- malonate in 500 ml. of hot absolute ethanol, is chromatographed under the same conditions and using the same apparatus described in Example 1. The eluate is concentrated in vacuo at a temperature not exceeding 40C. The residue is taken up with diethyl ether, washed with a 10 percent solution of sodium bicarbonate and dried over sodium sulphate. The solvent is evaporated and the residue is distilled in vacuo, collecting the fraction boiling at lO5l07C/0.2 mm. A colorless oil is obtained consisting of'ethyl p-ethoxyphenyl(fluoro)-acetate. Yield 87 percent; n,, 1,5095.

Calcd. for C H FO C, 63,69; Found: C, 63,59-

According to method A.

In a solution of 19.5 g. (60 mmole) of diethyl fluoro(- p-isobutylphenyl)-malonate, in ml. of absolute ethanol, 112 ml. (60 mmole) ofa 3 percent ethanolic solution of potassium hydroxide are added drop by drop at room temperature during 7 hours. A volume of 1.5 liters of diethyl ether is added and the mixture is allowed to stand overnight. After filtering the precipitated salts the solution is concentrated in vacuo at a temperature not exceeding 40C. The residue is distilled in vacuo and the fraction boiling at 93l01C/O.2 mm. is collected. An oil is obtained, consisting of ethyl fluoro(pisobutylphenyl)-acetate. Yield 74 percent; n 1,4958.

Calcd. for C H FO Found:

EXAMPLE 4 Preparation of ethyl fluoro( l-naphthyl)-acetate.

1. According to method A.

To a solution of 4.3 g. (14 mmole) of diethyl fluoro( I-naphthyU-malonate in ml. of absolute ethanol 26.5 ml. ofa 3 percent ethanolic solution of potassium hydroxide are added at room temperature during 7 hours. A volume of 3 l. of diethyl ether is added and the mixture is allowed to stand overnight. The precipitated salts are filtered off, then the filtrate is concentrated to dryness in vacuo at a temperature not exceeding 40C. An oily residue is obtained.

2. According to method B.

It is prepared working under the same conditions described in example 1. A quantity of 12.7 f. (40 mmole) of the monopotassium salt of the monoethyl fluoro( lnaphthyl)-malonate, dissolved at 40C in 1.1 liters of absolute ethanol, are passed through a column of 340 m1. of amberlite IR 120 (H). The eluate is concentrated and the residue taken up with diethylether. The ether solution is washed with a 10 percent solution of sodium bicarbonate, dried over sodium sulphate and concentrated. The residue is distilled in vacuo, collecting the fraction boiling at l20l25C/O.2 mm. An oil is obtained consisting of ethyl fluoro(1-naphthy1)-acetate. Yield 84 percent; n 1,5803.

Calcd. for C H FO C, Found: C

EXAMPLE 5 Preparation of ethyl 2-dibenzofurany1(fluoro)-acetate.

According to method A.

To a solution of 9.15 g. (26,5 mmole) of diethyl 2- dibenzofurany1(fluoro)-ma1onate, in 250 ml. of absolute ethanol, 48.5 ml. ofa 3 percent potassium hydroxide solution in ethanol are added during 7 hours. A volume of 3 liters of diethyl ether is added and the mixture Calcd. for C H FO Found:

C, 70,57; H, 4,61; F, 6,97. C, 70,34; H, 5,00, F, 6,7.

We claim: 1. The compound ethyl fluoro-(2-dibenzofurany1)- acetate. 

1. THE COMPOUND ETHYL FLUORO-(2-DIBENZOFURANYL)-ACETATE. 